Acyclovir is an acyclic analogue of the natural nucleoside 2′-deoxyguanosine which possesses antiviral activity against the Herpes virus, a DNA virus.
Mild genital and labial herpes infections cause the appearance of local blisters and ulcers of limited size, which may not require any pharmacological treatment, although the first-line treatment for mild herpes infections is local administration of 5% acyclovir.
Serious genital and labial herpes infections can give rise to extensive blistering and ulceration of the mucous membranes, sometimes accompanied by fever, lymphadenopathy and dysuria, and in some cases may also involve the cervix (Rawls, W. E. (1985). Herpes Simplex viruses. In “Virology” chapter 26, pp 527-561. Ed. Fields B. N., Knipe, D. M., Chanock, R. M., Melnick, J. L., Roizman, B., Raven Press, New York.). The preferred treatment for the said disorder in that case is oral administration of acyclovir (200 mg once a day), always associated with local treatment.
Acyclovir is administered locally in conventional dosage forms with a dosage pattern of five applications a day; however, this dose is unable to maintain therapeutically effective levels of the drug at the site of action for a long period. Local treatment often fails due to the active physiological removal mechanisms (physiological secretions and/or mechanical stress) which cause incorrect distribution of the drug in the mucocutaneous area affected by the infection, in view of the numerous applications required to maintain efficacious levels of the drug at the site of application.
To meet therapeutic requirements, formulations containing acyclovir which are intended for topical administration in areas affected by herpes lesions should consequently have good properties of adherence to the mucous membranes and high resistance to physiological removal mechanisms, so as to maintain close, protracted contact between the formulation and the mucosa or epidermis affected by the herpes lesions.
The mucoadhesive properties of semisolid drug delivery systems are due to the presence of semi-synthetic or natural polymers able to interact with the biological substrates. In contact with aqueous solvents, these polymers form hydrophilic gels characterised by a lattice in which water molecules are trapped.
Polyacrylic acids (PAA) are synthetic polymers widely used in local drug delivery systems. PAAs are characterised by good mucoadhesive properties and excellent thickening efficiency. Their crosslinked structure and substantial insolubility in water make PAAs suitable for use in controlled drug release systems (Singla A. K. et al., 2000, Drug Dev. Ind. Pharm. 29: 913-924).
Hyaluronic acid (HA) is a heteropolysaccharide composed of alternate residues of D-glucuronic acid and N-acetyl-D-glucosamine. It is a linear-chain polymer, with a molecular weight that can range between 50,000 and 13×106 Da, depending on the source from which it is obtained and the preparation methods used.
It is a glycosaminoglycan present in nature in the pericellular gels, the synovial fluid of the joints, the vitreous humour and the umbilical cord, and is widely distributed in the extracellular matrix of the connective tissues. HA is believed to perform regulatory and structural functions in the reconstruction of the tissues through modulation of fibroblast proliferation and the inflammatory response (Goa K. L. et al., 1994, Drugs, 47: 536-566).
HA therefore plays an important role in the biological organism and, together with those described above, also acts as mechanical support for the cells of many tissues such as skin, tendons, muscles and cartilage.
Mucoadhesive formulations containing synthetic polymers, including polyacrylic acids, and hyaluronic acid have already been disclosed as drug delivery systems in IT 1273742; however, the preferred polymer is Polycarbophil (polyacrylic acid crosslinked with divinyl glycol) in association with high molecular weight hyaluronic acid.
This invention relates to new topical formulations of acyclovir in the form of hydrophilic gels which are highly bioadhesive due to the presence of hyaluronic acid (with low molecular weight) or derivatives thereof, in association with polyacrylic acid for the treatment of all mucocutaneous lesions caused by Herpes Simplex or Herpes Zoster.